SEARCH · Search NASA

Results for “conformance assessment”

Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 199 records · Page 11

All sources NASA NTRS DOE OSTI

DOE OSTI2023

Residual estimation for grid modification in wall-modeled large eddy simulation using unstructured high-order methods

Here, the accuracy and computational cost of a large eddy simulation are highly dependent on the computational grid. Building optimal grids manually from a priori knowledge is not feasible in most practical use cases; instead, solution-adaptive strategies can provide a robust and cost-efficient method to generate a grid with the desired accuracy. We adapt the residual estimation algorithm developed by Toosi and Larsson for Discontinuous Galerkin Spectral Elements Methods (DGSEM) to guide the grid-adaptation process. The core of the method is the computation of the estimated modeling residual using the polynomial basis functions used in DGSEM, and the averaging of the estimated residual over each element. The final method is assessed in multiple channel flow test cases and for the transonic flow over an airfoil, in both cases making use of mortar interfaces between elements with hanging nodes. The method is found to be robust and reliable, and to provide solutions on grids with significantly fewer elements at comparable accuracy compared to when using human-generated grids.

97 MATHEMATICS AND COMPUTING↗

NASA NTRS1996

Simulated 'On-Line' Wear Metal Analysis of Lubricating Oils by X-Ray Fluorescence Spectroscopy

The objective of this project was to assess the sensitivity of X-ray Fluorescence Spectroscopy (XFS) for quantitative evaluation of metal particle content in engine oil suspensions and the feasibility of real-time, dynamic wear metal analysis. The study was focused on iron as the majority wear metal component. Variable parameters were: particle size, particle concentration and oil velocity. A commercial XFS spectrometer equipped with interchangeable static/dynamic (flow cell) sample chambers was used. XFS spectra were recorded for solutions of Fe-organometallic standard and for a series of DTE oil suspensions of high purity spherical iron particles of 2g, 4g, and 8g diameter, at concentrations from 5 ppm to 5,000 ppm. Real contaminated oil samples from Langley Air Force Base aircraft engines and NASA Langley Research Center wind tunnels were also analyzed. The experimental data conform the reliability of XFS as the analytical method of choice for this project. Intrinsic inadequacies of the instrument for precise analytic work at low metal concentrations were identified as being related to the particular x-ray beam definition, system geometry, and flow-cell materials selection. This work supports a proposal for the design, construction and testing of a conceptually new, miniature XFS spectrometer with superior performance, dedicated to on-line, real-time monitoring of lubricating oils in operating engines. Innovative design solutions include focalization of the incident x-ray beam, non-metal sample chamber, and miniaturization of the overall assembly. The instrument would contribute to prevention of catastrophic engine failures. A proposal for two-year funding has been presented to NASA Langley Research Center Internal Operation Group (IOG) Management, to continue the effort begun by this summer's project.

Kelliher, Warren C.↗

NASA NTRS2000

Wind Prediction Accuracy for Air Traffic Management Decision Support Tools

The performance of Air Traffic Management and flight deck decision support tools depends in large part on the accuracy of the supporting 4D trajectory predictions. This is particularly relevant to conflict prediction and active advisories for the resolution of conflicts and the conformance with of traffic-flow management flow-rate constraints (e.g., arrival metering / required time of arrival). Flight test results have indicated that wind prediction errors may represent the largest source of trajectory prediction error. The tests also discovered relatively large errors (e.g., greater than 20 knots), existing in pockets of space and time critical to ATM DST performance (one or more sectors, greater than 20 minutes), are inadequately represented by the classic RMS aggregate prediction-accuracy studies of the past. To facilitate the identification and reduction of DST-critical wind-prediction errors, NASA has lead a collaborative research and development activity with MIT Lincoln Laboratories and the Forecast Systems Lab of the National Oceanographic and Atmospheric Administration (NOAA). This activity, begun in 1996, has focussed on the development of key metrics for ATM DST performance, assessment of wind-prediction skill for state of the art systems, and development/validation of system enhancements to improve skill. A 13 month study was conducted for the Denver Center airspace in 1997. Two complementary wind-prediction systems were analyzed and compared to the forecast performance of the then standard 60 km Rapid Update Cycle - version 1 (RUC-1). One system, developed by NOAA, was the prototype 40-km RUC-2 that became operational at NCEP in 1999. RUC-2 introduced a faster cycle (1 hr vs. 3 hr) and improved mesoscale physics. The second system, Augmented Winds (AW), is a prototype en route wind application developed by MITLL based on the Integrated Terminal Wind System (ITWS). AW is run at a local facility (Center) level, and updates RUC predictions based on an optimal interpolation of the latest ACARS reports since the RUC run. This paper presents an overview of the study's results including the identification and use of new large mor wind-prediction accuracy metrics that are key to ATM DST performance.

Cole, Rod↗

DOE OSTI2022

Tailoring Corrosion Resistance of Additively Manufactured Metals with Atomic Layer Deposition

The goal of this work is to develop a scalable post-manufacturing capability at LANL that utilizes atomic layer deposition (ALD) for corrosion-resistant coatings onto additively manufactured (AM) metals. This will provide fundamentally new and essential capabilities towards the interchangeability of AM metals with traditionally wrought or machined material. This will be accomplished by (1) formulating novel ALD precursor doses and film thicknesses onto as-printed coupons of AM metals and (2) providing electrochemical characterization of corrosion susceptibility as a function of deposited film thickness. While ALD is well-established, the unique aspect (risk) of this work is application to rough AM surfaces. This risk is mitigated by repeating ALD deposition cycles, where thicker coatings laterally branch, resulting in a uniform coating. This risk will be assessed in the phase 1 feasibility study, wherein the application of ALD coatings to small AM coupon surfaces will be demonstrated using existing hardware and characterization tools at Sigma. This study alone will provide ground-breaking insight on the compatibility of ALD coating techniques with AM metals. Going beyond the phase 1 study, a standalone deposition chamber will be built, so full AM components can be coated and tested. While this MFR investment is focused on corrosion mitigation, it is critical to highlight external benefits of this technique outside the scope of this proposed study. ALD has extraordinary universality, whereby almost any material can be given almost any coating or graded density coating with atomic precision; and, the only limiting factors to scalability is the size of the dosing chamber. The self-limiting reactions intrinsic to ALD offers high conformity to part geometry and tolerance, even for internal surfaces where electroplating or conventional chemical vapor deposition falls short due to differential diffusion. This uniquely positions ALD at the forefront of post-manufacturing strategies for AM components, especially for those with complex geometry and internal surfaces.

36 MATERIALS SCIENCE↗

NASA NTRS1998

The Effects of Impurities on Protein Crystal Growth and Nucleation: A Preliminary Study

Kubota and Mullin (1995) devised a simple model to account for the effects of impurities on crystal growth of small inorganic and organic molecules in aqueous solutions. Experimentally, the relative step velocity and crystal growth of these molecules asymptotically approach zero or non-zero values with increasing concentrations of impurities. Alternatively, the step velocity and crystal growth can linearly approach zero as the impurity concentration increases. The Kubota-Mullin model assumes that the impurity exhibits Langmuirian adsorption onto the crystal surface. Decreases in step velocities and subsequent growth rates are related to the fractional coverage (theta) of the crystal surface by adsorbed impurities; theta = Kx / (I +Kx), x = mole fraction of impurity in solution. In the presence of impurities, the relative step velocity, V/Vo, and the relative growth rate of a crystal face, G/Go, are proposed to conform to the following equations: V/Vo approx. = G/Go = 1 - (alpha)(theta). The adsorption of impurity is assumed to be rapid and in quasi-equilibrium with the crystal surface sites available. When the value of alpha, an effectiveness factor, is one the growth will asymptotically approach zero with increasing concentrations of impurity. At values less than one, growth approaches a non-zero value asymptotically. When alpha is much greater than one, there will be a linear relationship between impurity concentration and growth rates. Kubota and Mullin expect alpha to decrease with increasing supersaturation and shrinking size of a two dimensional nucleus. It is expected that impurity effects on protein crystal growth will exhibit behavior similar to that of impurities in small molecule growth. A number of proteins were added to purified chicken egg white lysozyme, the effect on crystal nucleation and growth assessed.

Schall, Constance A.↗

NASA NTRS2018

Pairwise Trajectory Management (PTM): Concept Description and Documentation

Pairwise Trajectory Management (PTM) is an Interval Management (IM) concept that utilizes airborne and ground-based capabilities to enable the implementation of airborne pairwise spacing capabilities in oceanic regions. The goal of PTM is to use airborne surveillance and tools to manage an "at or greater than" inter-aircraft spacing. Due to the accuracy of Automatic Dependent Surveillance-Broadcast (ADS-B) information and the use of airborne spacing guidance, the minimum PTM spacing distance will be less than distances a controller can support with current automation systems that support oceanic operations. Ground tools assist the controller in evaluating the traffic picture and determining appropriate PTM clearances to be issued. Avionics systems provide guidance information that allows the flight crew to conform to the PTM clearance issued by the controller. The combination of a reduced minimum distance and airborne spacing management will increase the capacity and efficiency of aircraft operations at a given altitude or volume of airspace. This document provides an overview of the proposed application, a description of several key scenarios, a high level discussion of expected air and ground equipment and procedure changes, a description of a NASA human-machine interface (HMI) prototype for the flight crew that would support PTM operations, and initial benefits analysis results. Additionally, included as appendices, are the following documents: the PTM Operational Services and Environment Definition (OSED) document and a companion "Future Considerations for the Pairwise Trajectory Management (PTM) Concept: Potential Future Updates for the PTM OSED" paper, a detailed description of the PTM algorithm and PTM Limit Mach rules, initial PTM safety requirements and safety assessment documents, a detailed description of the design, development, and initial evaluations of the proposed flight crew HMI, an overview of the methodology and results of PTM pilot training requirements focus group and human-in-the-loop testing activities, and the PTM Pilot Guide.

Jones, Kenneth M.↗

DOE OSTI2024

Structural studies of intrinsically disordered MLL -fusion protein AF9 in complex with peptidomimetic inhibitors

AF9 (MLLT3) and its paralog ENL(MLLT1) are members of the YEATS family of proteins with important role in transcriptional and epigenetic regulatory complexes. These proteins are two common MLL fusion partners in MLL -rearranged leukemias. The oncofusion proteins MLL-AF9/ENL recruit multiple binding partners, including the histone methyltransferase DOT1L, leading to aberrant transcriptional activation and enhancing the expression of a characteristic set of genes that drive leukemogenesis. The interaction between AF9 and DOT1L is mediated by an intrinsically disordered C-terminal ANC1 homology domain (AHD) in AF9, which undergoes folding upon binding of DOT1L and other partner proteins. We have recently reported peptidomimetics that disrupt the recruitment of DOT1L by AF9 and ENL, providing a proof-of-concept for targeting AHD and assessing its druggability. Intrinsically disordered proteins, such as AF9 AHD, are difficult to study and characterize experimentally on a structural level. In this study, we present a successful protein engineering strategy to facilitate structural investigation of the intrinsically disordered AF9 AHD domain in complex with peptidomimetic inhibitors by using maltose binding protein (MBP) as a crystallization chaperone connected with linkers of varying flexibility and length. The strategic incorporation of disulfide bonds provided diffraction-quality crystals of the two disulfide-bridged MBP–AF9 AHD fusion proteins in complex with the peptidomimetics. These successfully determined first series of 2.1–2.6 Å crystal complex structures provide high-resolution insights into the interactions between AHD and its inhibitors, shedding light on the role of AHD in recruiting various binding partner proteins. We show that the overall complex structures closely resemble the reported NMR structure of AF9 AHD/DOT1L with notable difference in the conformation of the β-hairpin region, stabilized through conserved hydrogen bonds network. These first series of AF9 AHD/peptidomimetics complex structures are providing insights of the protein–inhibitor interactions and will facilitate further development of novel inhibitors targeting the AF9/ENL AHD domain.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2025

Role of the Mobile Active Site Flap in IMP Dehydrogenase Inhibitor Binding

Inosine 5′-monophosphate dehydrogenase (IMPDH) is a promising antibiotic target. This enzyme catalyzes the NAD-dependent oxidation of inosine 5′-monophosphate (IMP) to xanthosine 5′-monophosphate (XMP), which is the rate-limiting step in guanine nucleotide biosynthesis. Bacterial IMPDH-specific inhibitors have been developed that bind to the NAD + site. These inhibitors display varied affinities to different bacterial IMPDHs that are not easily rationalized by X-ray crystal structures of enzyme–inhibitor complexes. Inspection of X-ray crystal structures of 25 enzyme–inhibitor complexes, including 10 newly described, suggested that a mobile active site flap may be a structural determinant of inhibitor potency. Saturation transfer difference NMR experiments also suggested that the flap may contact the inhibitors to varying extents in different IMPDHs. Flap residue Leu413 contacted some inhibitors but was not structured in the crystal structures of other inhibitor complexes. The substitution of Leu413 with Phe or Ala in Bacillus anthracis IMPDH had inhibitor-selective effects, suggesting residue 413 could be a structural determinant of affinity. Curiously, the Ala substitution increased the potency of most inhibitors, even those that contacted Leu413 in the crystal structures. Presteady-state and steady-state kinetics experiments showed that the Leu413Ala substitution had comparable effects on inhibitor binding to the noncovalent E·IMP complex and the covalent intermediate E-XMP*, suggesting that the flap had similar interactions in both complexes. These results demonstrate that contacts do not necessarily indicate favorable interactions, and poorly structured mobile regions should not be discounted when assessing binding determinants.

Conformation↗

NASA NTRS2018

An Integrated Platform for Mission Performance: Goddard Space Flight Center's Meta Information System

Successful management of NASA Goddard Space Flight Centers portfolio of mission projects (i.e. spacecraft, spacecraft instruments / subsystems, and ground systems) depends upon numerous processes, data and information resources coming together throughout the life-cycle of the projects to enable sound decision-making, risk reduction, conformance with requirements and continual improvement. In the summer of 2012, GSFC SMA management recognized that the set of legacy data systems used to support the SMA mission and responsibilities at GSFC were not effective, integrated nor on par with best practices. Accordingly, GSFC SMA management launched a project to transform the GSFC electronic management system to create and deploy an integrated, state-of-the-market information system for process performance, data management and analytics that is currently operating in support of GSFC overall mission performance. The information system, known as Meta, provides controlled, process-based applications, integrated data management, and analytics for a robust set of integrated applications. Since the inception of the project, a lean, award-winning SMA project team has thus far designed, configured and managed the system to serve as an integrated platform for 18 applications that support key processes for GSFC and the Science Mission Directorate at NASA headquarters, such as internal Management System assessments, Supplier Assessments, Supplier Research & Analysis, Problem Reporting for in-house mission projects, On-orbit Anomaly Reporting for GSFC-operated spacecraft, GSFC Project Life-Cycle Reviews, Risk Management and Reporting, and SMA Project Team Reporting. The system has experienced steady growth in utilization with 1,917 users (NASA employees and support contractor personnel) and 44 gigabytes of data and related files managed by the system as of the end of April 2018. Overall, Meta has achieved increasing levels of process management and real-time data / information integration to enable improved process performance, richer analytics and informed decision-making. This paper will present and examine the need, goals, approach and design driving the management and operation of the Meta information system and its ongoing growth as an integrated platform for advancing NASA mission performance.

Integration↗

NASA NTRS2013

Robust Platinum Resistor Thermometer (PRT) Sensors and Reliable Bonding for Space Missions

Platinum resistance thermometers (PRTs) provide accurate temperature measurements over a wide temperature range and are used extensively on space missions due to their simplicity and linearity. A standard on spacecraft, PRTs are used to provide precision temperature control and vehicle health assessment. This paper reviews the extensive reliability testing of platinum resistor thermometer sensors (PRTs) and bonding methods used on the Mars Science Laboratory (MSL) mission and for the upcoming Soil Moisture Active Passive (SMAP) mission. During the Mars Exploration Rover (MER) mission, several key, JPL-packaged PRTs failed on those rovers prior to and within 1-Sol of landing due to thermally induced stresses. Similar failures can be traced back to other JPL missions dating back thirty years. As a result, MSL sought out a PRT more forgiving to the packaging configurations used at JPL, and extensively tested the Honeywell HRTS-5760-B-U-0-12 sensor to successfully demonstrate suitable robustness to thermal cycling. Specifically, this PRT was cycled 2,000 times, simulating three Martian winters and summers. The PRTs were bonded to six substrate materials (Aluminum 7050, treated Magnesium AZ231-B, Stainless Steel 304, Albemet, Titanium 6AL4V, and G-10), using four different aerospace adhesives--two epoxies and two silicones--that conformed to MSL's low out-gassing requirements. An additional epoxy was tested in a shorter environmental cycling test, when the need for a different temperature range adhesive was necessary for mobility and actuator hardware late in the fabrication process. All of this testing, along with electrostatic discharge (ESD) and destructive part analyses, demonstrate that this PRT is highly robust, and not subject to the failure of PRTs on previous missions. While there were two PRTs that failed during fabrication, to date there have been no in-flight PRT failures on MSL, including those on the Curiosity rover. Since MSL, the sensor has gone through a change in construction such that the manufacturer significantly restricts the minimum temperature. However, significant subsequent testing was performed with this new version of the part to show that it indeed is still robust to at least Mars minimum temperatures of -135(sup o)C. The additional completed testing will be described. This work has resulted in a successful sensor package qualification and a reliable bonding method suitable for use over large temperature extremes.

dectector↗

NASA NTRS2013

Robust Platinum Resistor Thermometer (PRT) Sensors and Reliable Bonding for Space Missions

Platinum resistance thermometers (PRTs) provide accurate temperature measurements over a wide temperature range and are used extensively on space missions due to their simplicity and linearity. A standard on spacecraft, PRTs are used to provide precision temperature control and vehicle health assessment. This paper reviews the extensive reliability testing of platinum resistor thermometer sensors (PRTs) and bonding methods used on the Mars Science Laboratory (MSL) mission and for the upcoming Soil Moisture Active Passive (SMAP) mission. During the Mars Exploration Rover (MER) mission, several key, JPL-packaged PRTs failed on those rovers prior to and within 1-Sol of landing due to thermally induced stresses. Similar failures can be traced back to other JPL missions dating back thirty years. As a result, MSL sought out a PRT more forgiving to the packaging configurations used at JPL, and extensively tested the Honeywell HRTS-5760-B-U-0-12 sensor to successfully demonstrate suitable robustness to thermal cycling. Specifically, this PRT was cycled 2,000 times, simulating three Martian winters and summers. The PRTs were bonded to six substrate materials (Aluminum 7050, treated Magnesium AZ231-B, Stainless Steel 304, Albemet, Titanium 6AL4V, and G-10), using four different aerospace adhesives--two epoxies and two silicones--that conformed to MSL's low out-gassing requirements. An additional epoxy was tested in a shorter environmental cycling test, when the need for a different temperature range adhesive was necessary for mobility and actuator hardware late in the fabrication process. All of this testing, along with electrostatic discharge (ESD) and destructive part analyses, demonstrate that this PRT is highly robust, and not subject to the failure of PRTs on previous missions. While there were two PRTs that failed during fabrication, to date there have been no in-flight PRT failures on MSL, including those on the Curiosity rover. Since MSL, the sensor has gone through a change in construction such that the manufacturer significantly restricts the minimum temperature. However, significant subsequent testing was performed with this new version of the part to show that it indeed is still robust to at least Mars minimum temperatures of -135 degrees Centigrade. The additional completed testing will be described. This work has resulted in a successful sensor package qualification and a reliable bonding method suitable for use over large temperature extremes

Platinum Resistor Thermometer (PRT)↗

DOE OSTI2021

Unsaturated Sulfur Crown Ethers Can Extract Mercury(II) and Show Promise for Future Copernicium(II) Studies: A Combined Experimental and Computational Study

The unsaturated hexathia-18-crown-6 (UHT18C6) molecule was investigated for the extraction of Hg(II) in HCl and HNO3 media. This extractant can be directly compared to the recently studied saturated hexathia-18-crown-6 (HT18C6). The default conformation of the S lone pairs in UHT18C6 is endodentate, where the pocket of the charge density, according to the crystal structures, is oriented toward the center of the ring, which should allow better extraction for Hg(II) compared to the exodentate HT18C6. Batch study experiments showed that Hg(II) had better extraction at low acid molarity (ca. 99% in HCl and ca. 95% in HNO 3 ), while almost no extraction was observed above 0.4 M HCl and 4 M HNO 3 (<5%). Speciation studies were conducted with the goal of delineating a plausible extraction mechanism. Density functional theory calculations including relativistic effects were carried out on both Hg(II)-encapsulated HT18C6 and UHT18C6 complexes to shed light on the binding strength and the nature of bonding. Our calculations offer insights into the extraction mechanism. In addition to Hg(II), calculations were performed on the hypothetical divalent Cn(II) ion, and showed that HT18C6 and UHT18C6 could extract Cn(II). Finally, the extraction kinetics were explored to assess whether this crown can extract the short-lived Cn(II) species in a future online experiment.

38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEA↗

DOE OSTI2022

Quantifying Errors in Effective Cluster Interactions of Lattice Gas Cluster Expansions

The promise of lattice gas (LG) cluster expansions (CEs) is that they can describe a given system property to any level of accuracy since the orthogonal “cluster basis functions” span the complete space of available configurations. Such an approach can be constructed to an arbitrarily large surface of a finite number of distinct adsorption sites. Unfortunately, this is only true for the case of an ideal, fixed lattice decorated with components at precise lattice points (the lattice “sites”) with no distortions or relaxations subsequently allowed. Since most systems, and surfaces specifically, do not conform to such an ideal set of constraints, errors in LG CEs must be expected or CE convergence severely hampered. Beyond this, numerical errors in the provided data can complicate the proper construction of a truly predictive and/or physically significant CE. In this work, we show here how reliance on typical statistical tools like confidence intervals cannot be expected to provide an accurate representation of the uncertainty of effective cluster interactions (ECIs) in the CE due to the nature of the target ab initio data and the nature of CEs themselves. We develop a method for estimating these errors that does not rely on statistical assumptions about the model or data. We then use these ECI errors to quantify fundamental consequences on the uncertainty of ECIs in CEs built from O/Fe(100) data whose surface and adsorbates have been allowed to relax in a typical manner and from O/Fe(100) data whose surface and adsorbates are fixed in ideal lattice positions. We also quantify the effect of using a different density functional theory exchange–correlation functional, using these ECI errors to assess the significance in any deviations. In both cases, our method is shown to have remarkable utility in the quantification of errors in the ECIs of CEs. While we stick to the lattice gas convention in this work, the method is equally applicable to the Ising convention or, in principle, any linear model of sufficient complexity.

08 HYDROGEN↗

NASA NTRS1995

Asymmetric structure of five and six membered DNA hairpin loops

The tertiary structure of nucleic acid hairpins was elucidated by means of the accessibility of the single-strand-specific nuclease from mung bean. This molecular probe has proven especially useful in determining details of the structural arrangement of the nucleotides within a loop. In this study 3'-labeling is introduced to complement previously used 5'-labeling in order to assess and to exclude possible artifacts of the method. Both labeling procedures result in mutually consistent cleavage patterns. Therefore, methodological artifacts can be excluded and the potential of the nuclease as structural probe is increased. DNA hairpins with five and six membered loops reveal an asymmetric loop structure with a sharp bend of the phosphate-ribose backbone between the second and third nucleotide on the 3'-side of a loop. These hairpin structures differ from smaller loops with 3 or 4 members, which reveal this type of bend between the first and second 3' nucleotide, and resemble with respect to the asymmetry anticodon loops of tRNA.

NASA Discipline Exobiology↗

DOE OSTI2022

Chelating Rare-Earth Metals (Ln 3+ ) and 225 Ac 3+ with the Dual-Size-Selective Macrocyclic Ligand Py 2 -Macrodipa

Radioisotopes of metallic elements, or radiometals, are widely employed in both therapeutic and diagnostic nuclear medicine. For this application, chelators that efficiently bind the radiometal of interest and form a stable metal–ligand complex with it are required. Toward the development of new chelators for nuclear medicine, we recently reported a novel class of 18-membered macrocyclic chelators that is characterized by their ability to form stable complexes with both large and small rare-earth metals (Ln 3+ ), a property referred to as dual size selectivity. A specific chelator in this class called py-macrodipa, which contains one pyridyl group within its macrocyclic core, was established as a promising candidate for 135 La 3+ , 213 Bi 3+ , and 44 Sc 3+ chelation. Building upon this prior work, here we report the synthesis and characterization of a new chelator called py 2 -macrodipa with two pyridyl units fused into the macrocyclic backbone. Its coordination chemistry with the Ln 3+ series was investigated by NMR spectroscopy, X-ray crystallography, density functional theory (DFT) calculations, analytical titrations, and transchelation assays. These studies reveal that py 2 -macrodipa retains the expected dual size selectivity and possesses an enhanced thermodynamic affinity for all Ln 3+ compared to py-macrodipa. By contrast, the kinetic stability of Ln 3+ complexes with py 2 -macrodipa is only improved for the light, large Ln 3+ ions. Based upon these observations, we further assessed the suitability of py 2 -macrodipa for use with 225 Ac 3+ , a large radiometal with valuable properties for targeted α therapy. Radiolabeling and stability studies revealed py 2 -macrodipa to efficiently incorporate 225 Ac 3+ and to form a complex that is inert in human serum over 3 weeks. Although py 2 -macrodipa does not surpass the state-of-the-art chelator macropa for 225 Ac 3+ chelation, it does provide another effective 225 Ac 3+ chelator. Furthermore, these studies shed light on the fundamental coordination chemistry of the Ln 3+ series and may inspire future chelator design efforts.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

NASA NTRS2007

Interactions of the SAP Domain of Human Ku70 with DNA Substrate: A Molecular Dynamics Study

NASA is developing a systems biology approach to improve the assessment of health risks associated with space radiation. The primary toxic and mutagenic lesion following radiation exposure is the DNA double strand break (DSB), thus a model incorporating proteins and pathways important in response and repair of this lesion is critical. One key protein heterodimer for systems models of radiation effects is the Ku70/80 complex. The Ku70/80 complex is important in the initial binding of DSB ends following DNA damage, and is a component of nonhomologous end joining repair, the primary pathway for DSB repair in mammalian cells. The SAP domain of Ku70 (residues 556-609), contains an a helix-extended strand-helix motif and similar motifs have been found in other nucleic acid-binding proteins critical for DNA repair. However, the exact mechanism of damage recognition and substrate specificity for the Ku heterodimer remains unclear in part due to the absence of a high-resolution structure of the SAP/DNA complex. We performed a series of molecular dynamics (MD) simulations on a system with the SAP domain of Ku70 and a 10 base pairs DNA duplex. Large-scale conformational changes were observed and some putative binding modes were suggested based on energetic analysis. These modes are consistent with previous experimental investigations. In addition, the results indicate that cooperation of SAP with other domains of Ku70/80 is necessary to explain the high affinity of binding as observed in experiments.

Hu, Shaowen↗

DOE OSTI2024

Evaluating the impact of anatomical and physiological variability on human equivalent doses using PBPK models

Abstract Addressing human anatomical and physiological variability is a crucial component of human health risk assessment of chemicals. Experts have recommended probabilistic chemical risk assessment paradigms in which distributional adjustment factors are used to account for various sources of uncertainty and variability, including variability in the pharmacokinetic behavior of a given substance in different humans. In practice, convenient assumptions about the distribution forms of adjustment factors and human equivalent doses (HEDs) are often used. Parameters such as tissue volumes and blood flows are likewise often assumed to be lognormally or normally distributed without evaluating empirical data for consistency with these forms. In this work, we performed dosimetric extrapolations using physiologically based pharmacokinetic (PBPK) models for dichloromethane (DCM) and chloroform that incorporate uncertainty and variability to determine if the HEDs associated with such extrapolations are approximately lognormal and how they depend on the underlying distribution shapes chosen to represent model parameters. We accounted for uncertainty and variability in PBPK model parameters by randomly drawing their values from a variety of distribution types. We then performed reverse dosimetry to calculate HEDs based on animal points of departure for each set of sampled parameters. Corresponding samples of HEDs were tested to determine the impact of input parameter distributions on their central tendencies, extreme percentiles, and degree of conformance to lognormality. This work demonstrates that the measurable attributes of human variability should be considered more carefully and that generalized assumptions about parameter distribution shapes may lead to inaccurate estimates of extreme percentiles of HEDs.

Toxicology↗

NASA NTRS2007

Interactions of the C-terminal Domain of Human Ku70 with DNA Substrate: A Molecular Dynamics Study

NASA is developing a systems biology approach to improve the assessment of health risks associated with space radiation. The primary toxic and mutagenic lesion following radiation exposure is the DNA double strand break (DSB), thus a model incorporating proteins and pathways important in response and repair of this lesion is critical. One key protein heterodimer for systems models of radiation effects is the Ku(sub 70/80) complex. The Ku70/80 complex is important in the initial binding of DSB ends following DNA damage, and is a component of nonhomologous end joining repair, the primary pathway for DSB repair in mammalian cells. The C-terminal domain of Ku70 (Ku70c, residues 559-609), contains an helix-extended strand-helix motif and similar motifs have been found in other nucleic acid-binding proteins critical for DNA repair. However, the exact mechanism of damage recognition and substrate specificity for the Ku heterodimer remains unclear in part due to the absence of a high-resolution structure of the Ku70c/DNA complex. We performed a series of molecular dynamics (MD) simulations on a system with the subunit Ku70c and a 14 base pairs DNA duplex, whose starting structures are designed to be variable so as to mimic their different binding modes. By analyzing conformational changes and energetic properties of the complex during MD simulations, we found that interactions are preferred at DNA ends, and within the major groove, which is consistent with previous experimental investigations. In addition, the results indicate that cooperation of Ku70c with other subunits of Ku(sub 70/80) is necessary to explain the high affinity of binding as observed in experiments.

Hu, Shaowen↗